Clarithromycin (clarithromycin 250 mg) Dailymed

Recent Major Changes Section

Contraindications, Lomitapide, Lovastatin, and Simvastatin (4.5)	9/2019
Warnings and Precautions, QT Prolongation (5.2)	11/2018
Warnings and Precautions, Serious Adverse Reactions Due to Concomitant Use with Other Drugs (5.4)	9/2019
Warnings and Precautions, Embryo-fetal Toxicity (5.7)	12/2018

1 Indications And Usage

Clarithromycin is a macrolide antimicrobial indicated for mild to moderate infections caused by designated, susceptible bacteria in the following:

• •Acute Bacterial Exacerbation of Chronic Bronchitis in Adults (1.1)
• •Acute Maxillary Sinusitis (1.2)
• •Community-Acquired Pneumonia (1.3)
• •Pharyngitis/Tonsillitis (1.4)
• •Uncomplicated Skin and Skin Structure Infections (1.5)
• •Acute Otitis Media in Pediatric Patients (1.6)
• •Treatment and Prophylaxis of Disseminated Mycobacterial Infections (1.7)
• • Helicobacter pylori Infection and Duodenal Ulcer Disease in Adults (1.8)

Limitations of Use:

To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin and other antibacterial drugs, clarithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.9)

1.1 Acute Bacterial Exacerbation of Chronic Bronchitis

Clarithromycin is indicated in adults for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae [see Indications and Usage (1.9) ].

1.2 Acute Maxillary Sinusitis

Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae [see Indications and Usage (1.9) ].

1.3 Community-Acqired Pneumonia

Clarithromycin is indicated [see Indications and Usage (1.9) ] for the treatment of mild to moderate infections caused by susceptible isolates due to:

• • Haemophilus influenzae (in adults)
• • Haemophilus parainfluenzae (in adults)
• • Moraxella catarrhalis (in adults)
• • Mycoplasma pneumoniae, Streptococcus pneumoniae, Chlamydophila pneumoniae (in adults and pediatric patients)

1.4 Pharyngitis/Tonsillitis

Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Streptococcus pyogenes as an alternative in individuals who cannot use first line therapy.

1.5 Uncomplicated Skin and Skin Structure Infections

Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Staphylococcus aureus, or Streptococcus pyogenes.

1.6 Acute Otitis Media

Clarithromycin is indicated in pediatric patients for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae [see Clinical Studies (14.2) ].

1.7 Treatment and Prophylaxis of Disseminated Mycobacterial Infections

Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Mycobacterium avium or Mycobacterium intracellulare in patients with advanced HIV infection [see Clinical Studies (14.1) ].

1.8 Infection and Duodenal Ulcer Disease

Clarithromycin is given in combination with other drugs in adults as described below to eradicate H. pylori. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.3) ].

• •Clarithromycin in combination with amoxicillin and PREVACID (lansoprazole) or PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to eradicate H. pylori.
• •Clarithromycin in combination with PRILOSEC (omeprazole) capsules are indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. Regimens which contain clarithromycin as the single antibacterial agent are more likely to be associated with the development of clarithromycin resistance among patients who fail therapy. Clarithromycin-containing regimens should not be used in patients with known or suspected clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting.

1.9 Limitations of Use

There is resistance to macrolides in certain bacterial infections caused by Streptococcus pneumoniae and Staphylococcus aureus. Susceptibility testing should be performed when clinically indicated.

1.10 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin and other antibacterial drugs, clarithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 Dosage And Administration

• •Adults: Clarithromycin 250 mg or 500 mg every 12 hours for 7 to14 days (2.2)
• • H. pylori eradication (in combination with lansoprazole/amoxicillin, omeprazole/amoxicillin, or omeprazole): Clarithromycin 500 mg every 8 or 12 hours for 10 to14 days. See full prescribing information (FPI) for additional information. (2.3)
• •Pediatric Patients: Clarithromycin 15 mg/kg/day divided every 12 hours for 10 days (2.4)
• •Mycobacterial Infections: Clarithromycin 500 mg every 12 hours; Clarithromycin 7.5 mg/kg up to 500 mg every 12 hours in pediatric patients (2.5)
• •Reduce dose in moderate renal impairment with concomitant atazanavir or ritonavir-containing regimens and in severe renal impairment (2.6)

2.1 Important Administration Instructions

Clarithromycin may be given with or without food.

2.2 Adult Dosage

The recommended dosages of clarithromycin for the treatment of mild to moderate infections in adults are uled in Table 1.

Table 1. Adult Dosage Guidelines

Infection	Dosage(Every 12 Hours)	Duration(Days)
Acute Bacterial Exacerbation of Chronic Bronchitis	250 to 500 mgFor M. catarrhalis and S. pneumoniae use 250 mg. For H. influenzae and H. parainfluenzae, use 500 mg.	7For H. parainfluenzae, the duration of therapy is 7 days. to 14
Acute Maxillary Sinusitis	500 mg	14
Community-acquired Pneumonia	250 mg	7For H. influenzae, the duration of therapy is 7 days. to 14
Pharyngitis/Tonsillitis	250 mg	10
Uncomplicated Skin and Skin Structure Infections	250 mg	7 to 14
Treatment and Prophylaxis of Disseminated Mycobacterium avium Disease [see Dosage and Administration (2.5) ]	500 mgClarithromycin therapy should continue if clinical response is observed. Clarithromycin can be discontinued when the patient is considered at low risk of disseminated infection.	-
H.pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence with Amoxicillin and Omeprazole or Lansoprazole [see Dosage and Administration (2.3) ]	500 mg	10 to 14
H.pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence with Omeprazole [see Dosage and Administration (2.3) ]	500 mg Every 8 Hours	14

2.3 Combination Dosing Regimens for Infection

• •Triple Therapy: Clarithromycin/Lansoprazole/Amoxicillin
  The recommended adult dosage is 500 mg clarithromycin, 30 mg lansoprazole, and 1 gram amoxicillin, all given every 12 hours for 10 or 14 days [see Indications and Usage (1.8) and Clinical Studies (14.3) ].
  
• •Triple Therapy: Clarithromycin/Omeprazole/Amoxicillin
  The recommended adult dosage is 500 mg clarithromycin, 20 mg omeprazole, and 1 gram amoxicillin; all given every 12 hours for 10 days. In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief [see Indications and Usage (1.8) and Clinical Studies (14.3) ].
  
• •Dual Therapy: Clarithromycin/Omeprazole
  The recommended adult dosage is 500 mg clarithromycin given every 8 hours and 40 mg omeprazole given once every morning for 14 days. An additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief [see Indications and Usage (1.8) and Clinical Studies (14.3) ].
  

2.4 Pediatric Dosage

The recommended daily dosage is 15 mg/kg/day divided every 12 hours for 10 days (up to the adult dose). Refer to dosage regimens for mycobacterial infections in pediatric patients for additional dosage information [see Dosage and Administration (2.5) ].

2.5 Dosage Regimens for Mycobacterial Infections

For the treatment of disseminated infection due to Mycobacterium avium complex (MAC), clarithromycin is recommended as the primary agent. Clarithromycin should be used in combination with other antimycobacterial drugs (e.g. ethambutol) that have shown in vitro activity against MAC or clinical benefit in MAC treatment [seeClinical Studies (14.1) ].

Adult Patients:

For treatment and prophylaxis of mycobacterial infections in adults, the recommended dose of clarithromycin is 500 mg every 12 hours.

Pediatric Patients:

For treatment and prophylaxis of mycobacterial infections in pediatric patients, the recommended dose is 7.5 mg/kg every 12 hours up to 500 mg every 12 hours [see Use in Specific Populations (8.4) and Clinical Studies (14.1) ].

Clarithromycin therapy should continue if clinical response is observed. Clarithromycin can be discontinued when the patient is considered at low risk of disseminated infection.

2.6 Dosage Adjustment in Patients with Renal Impairment

See Table 2 for dosage adjustment in patients with moderate or severe renal impairment with or without concomitant atazanavir or ritonavir-containing regimens [see Drug Interactions (7) ].

Table 2. Clarithromycin Dosage Adjustments in Patients with Renal Impairment

	Recommended Clarithromycin Dosage Reduction
Patients with Severe Renal Impairment (CLcr of <30 mL/min)	Reduce the Dosage of Clarithromycin by 50%
Patients with Moderate Renal Impairment (CLcr of 30 to 60 mL/min) Taking Concomitant Atazanavir or Ritonavir-containing Regimens	Reduce the Dosage of Clarithromycin by 50%
Patients with Severe Renal Impairment (CLcr of <30 mL/min) Taking Concomitant Atazanavir or Ritonavir-containing Regimens	Reduce the Dosage of Clarithromycin by 75%

2.7 Dosage Adjustment Due to Drug Interactions

Decrease the dose of clarithromycin by 50% when co-administered with atazanavir [see Drug Interactions (7) ]. Dosage adjustments for other drugs when co-administered with clarithromycin may be recommended due to drug interactions [see Drug Interactions (7) ].

• •Hypersensitivity to clarithromycin or any macrolide drug (4.1)
• •Cisapride and pimozide (4.2)
• •History of cholestatic jaundice/hepatic dysfunction with use of clarithromycin (4.3)
• •Colchicine in renal or hepatic impairment (4.4)
• •Lomitapide, lovastatin, and simvastatin (4.5)
• •Ergot alkaloids (ergotamine or dihydroergotamine) (4.6)

4.1 Hypersensitivity

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibacterial drugs [see Warnings and Precautions (5.1)].

4.2 Cisapride and Pimozide

Concomitant administration of clarithromycin with cisapride and pimozide is contraindicated [see Drug Interactions (7)].

There have been postmarketing reports of drug interactions when clarithromycin is co-administered with cisapride or pimozide, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by clarithromycin. Fatalities have been reported.

4.3 Cholestatic Jaundice/Hepatic Dysfunction

Clarithromycin is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin.

4.4 Colchicine

Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment.

4.5 Lomitapide, Lovastatin, and Simvastatin

Concomitant administration of clarithromycin with lomitapide is contraindicated due to potential for markedly increased transaminases [see Warnings and Precautions (5.4) and Drug Interactions (7)].

Concomitant administration of clarithromycin with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) is contraindicated, due to the increased risk of myopathy, including rhabdomyolysis [see Warnings and Precautions (5.4) and Drug Interactions (7)].

4.6 Ergot Alkaloids

Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated [see Drug Interactions (7)].

4.7 Contraindications for Co-administered Drugs

For information about contraindications of other drugs indicated in combination with clarithromycin, refer to their full prescribing information (contraindications section).

5 Warnings And Precautions

• • Severe Acute Hypersensitivity Reactions: Discontinue clarithromycin if occurs (5.1)
• • QT Prolongation: Avoid clarithromycin in patients with known QT prolongation or receiving drugs known to prolong the QT interval, ventricular arrhythmia (torsades de pointes), hypokalemia/hypomagnesemia, significant bradycardia, or taking Class IA or III antiarrhythmics (5.2)
• • Hepatotoxicity: Discontinue if signs and symptoms of hepatitis occur (5.3)
• •Serious adverse reactions can occur due to drug interactions of clarithromycin with colchicine, some lipid-lowering agents, some calcium channel blockers, and other drugs (5.4)
• •Risk of all-cause mortality one year or more after the end of treatment in patients with coronary artery disease. Balance this potential risk with the treatment benefits when prescribing clarithromycin in these patients (5.5)
• • Clostridium difficile Associated Diarrhea (CDAD): Evaluate if diarrhea occurs (5.6)
• • Embryo-Fetal Toxicity: Based on animal findings, Clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate (5.7)
• •Exacerbation of Myasthenia Gravis has been reported in patients receiving clarithromycin therapy (5.8)

5.1 Severe Acute Hypersensitivity Reactions

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, and acute generalized exanthematous pustulosis, discontinue clarithromycin therapy immediately and institute appropriate treatment.

5.2 QT Prolongation

• •Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported.

Avoid clarithromycin in the following patients:

• •Patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes
• •Patients receiving drugs known to prolong the QT interval [see also Contraindications (4.2)]
• •Patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia and in patients receiving Class IA (e.g., quinidine, procainamide, disopyramide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents

Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Use in Specific Populations (8.5)].

5.3 Hepatotoxicity

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur.

5.4 Serious Adverse Reactions Due to Concomitant Use with Other Drugs

Drugs metabolized by CYP3A4:

Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; markedly increased transaminases with lomitapide; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia and cardiac arrhythmias (e.g., torsades de pointes) with disopyramide; and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older. Use clarithromycin with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme. The use of clarithromycin with lomitapide, simvastatin, lovastatin, ergotamine, or dihydroergotamine is contraindicated [see Contraindications (4.5, 4.6) and Drug Interactions (7)].

Colchicine:

Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If co-administration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications (4.4) and Drug Interactions (7)].

Lomitapide:

Concomitant use of clarithromycin with lomitapide is contraindicated [see Contraindications (4.5)]. Lomitapide is metabolized by CYP3A4, and concomitant treatment with clarithromycin increases the plasma concentration of lomitapide, which increases the risk of elevation in transaminases [see Drug Interactions (7)]. If treatment with clarithromycin cannot be avoided, therapy with lomitapide must be suspended during the course of treatment.

HMG-CoA Reductase Inhibitors (Statins):

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated [see Contraindications (4.5)] as these statins are extensively metabolized by CYP3A4, and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Exercise caution when prescribing clarithromycin with atorvastatin or pravastatin. In situations where the concomitant use of clarithromycin with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided.

Oral Hypoglycemic Agents/Insulin:

The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended [see Drug Interactions (7)].

Quetiapine:

Use quetiapine and clarithromycin concomitantly with caution. Co-administration could result in increased quetiapine exposure and quetiapine related toxicities such as somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin [see Drug Interactions (7)].

Oral Anticoagulants:

There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. Monitor INR and prothrombin times frequently while patients are receiving clarithromycin and oral anticoagulants concurrently [see Drug Interactions (7)].

Benzodiazepines:

Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam and midazolam [see Drug Interactions (7)].

5.5 All-Cause Mortality in Patients With Coronary Artery Disease 1 to 10 Years After Clarithromycin Exposure

In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality one year or more after the end of treatment was observed in patients randomized to receive clarithromycin.¹ Clarithromycin for treatment of coronary artery disease is not an approved indication. The cause of the increased risk has not been established. Other epidemiologic studies evaluating this risk have shown variable results [see Adverse Reactions (6.1 )]. Consider balancing this potential risk with the treatment benefits when prescribing clarithromycin in patients who have suspected or confirmed coronary artery disease.

5.6 Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clarithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.7 Embryo-Fetal Toxicity

Based on findings from animal studies, Clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If clarithromycin is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or embryo fetal development, including fetal malformations, in pregnant animals administered oral clarithromycin [see Use in Specific Populations (8.1) ].

5.8 Exacerbation of Myasthenia Gravis

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.

5.9 Development of Drug Resistant Bacteria

Prescribing clarithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 Adverse Reactions

The following serious adverse reactions are described below and elsewhere in the labeling:

• •Acute Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• •QT Prolongation [see Warnings and Precautions (5.2)]
• •Hepatotoxicity [see Warnings and Precautions (5.3)]
• •Serious Adverse Reactions Due to Concomitant Use with Other Drugs [see Warnings and Precautions (5.4)]
• • Clostridium difficile Associated Diarrhea [see Warnings and Precautions (5.6)]
• •Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.8)]

Most frequent adverse reactions for both adult and pediatric populations in clinical trials: abdominal pain, diarrhea, nausea, vomiting, dysgeusia (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Based on pooled data across all indications, the most frequent adverse reactions for both adult and pediatric populations observed in clinical trials are abdominal pain, diarrhea, nausea, vomiting and dysgeusia. Also reported were dyspepsia, liver function test abnormal, anaphylactic reaction, candidiasis, headache, insomnia, and rash.

The subsequent subsections ul the most common adverse reactions for prophylaxis and treatment of mycobacterial infections and duodenal ulcer associated with H. pylori infection. In general, these profiles are consistent with the pooled data described above.

Prophylaxis of Mycobacterial Infections:

In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M. avium, it was often difficult to distinguish adverse reactions possibly associated with clarithromycin administration from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6 months for the clarithromycin group and 8.2 months for the placebo group.

Table 4. Incidence Rates (%) of Selected Adverse ReactionsIncludes those events possibly or probably related to study drug and excludes concurrent conditions. in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex

Body System 2% or greater Adverse Reaction Incidence Rates for either treatment group. Adverse Reaction	Clarithromycin (n=339) %	Placebo (n=339) %
Body as a Whole
Abdominal pain	5%	4%
Headache	3%	1%
Digestive
Diarrhea	8%	4%
Dyspepsia	4%	3%
Flatulence	2%	1%
Nausea	11%	7%
Vomiting	6%	3%
Skin & Appendages
Rash	3%	4%
Special Senses
Taste Perversion	8%Significant higher incidence compared to the placebo-treated group.	0.3%

Discontinuation due to adverse reactions occurred in 18% of patients receiving clarithromycin compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in clarithromycin treated patients include headache, nausea, vomiting, depression, and taste perversion.

Changes in Laboratory Values: Selected laboratory adverse experiences that were reported during therapy in greater than 2 % of adult patients treated with clarithromycin in a randomized double-blind clinical trial involving 682 patients are presented in Table 5.

In immunocompromised patients receiving prophylaxis against M. avium, evaluations of laboratory values were made by analyzing those values outside the seriously abnormal value (i.e., the extreme high or low limit) for the specified test.

Table 5. Percentage of PatientsIncludes only patients with baseline values within the normal range or borderline high (hematology variables) and within normal range or borderline low (chemistry variables). Exceeding Extreme Laboratory Values in Patients Receiving Prophylaxis Against M. avium Complex

		Clarithromycin 500 mg Twice a Day	Placebo
WBC Count	<1 x 109/L	2/103 (4%)	0/95
SGOT	>5 x ULNULN= Upper Limit of Normal	7/196 (4%)	5/208 (2%)
SGPT	>5 x ULN	6/217 (3%)	4/232 (2%)

Treatment of Mycobacterial Infections:

The adverse reaction profiles for both the 500 mg and 1000 mg twice a day dose regimens were similar.

In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse reactions possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness.

The following analysis summarizes experience during the first 12 weeks of therapy with clarithromycin. Data are reported separately for trial 1 (randomized, double-blind) and trial 2 (open-labeled, compassionate use) and also combined. Adverse reactions were reported less frequently in trial 2, which may be due in part to differences in monitoring between the two studies.

In adult patients receiving clarithromycin 500 mg twice a day, the most frequently reported adverse reactions, considered possibly or possibly related to study drug, with an incidence of 5% or greater, are uled below (Table 6). Approximately 8% of the patients who received 500 mg twice a day and 12% of the patients who received 1000 mg twice a day discontinued therapy due to drug related adverse reactions during the first 12 weeks of therapy; adverse reactions leading to discontinuation in at least 2 patients included nausea, vomiting, abdominal pain, diarrhea, rash, and asthenia.

Table 6. Selected Treatment-RelatedIncludes those events possibly or probably related to study drug and excludes concurrent conditions. Adverse Reaction Incidence Rates (%) in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg Twice a Day Clarithromycin Dose

Adverse Reaction	Trial 1 (n=53)	Trial 2 (n=255)	Combined (n=308)
Abdominal Pain	8	2	3
Diarrhea	9	2	3
Flatulence	8	0	1
Headache	8	0	2
Nausea	28	9	12
Rash	9	2	3
Taste Perversion	19	0	4
Vomiting	25	4	8

A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for mycobacterial infections. The most frequently reported adverse reactions excluding those due to the patient’s concurrent conditions were consistent with those observed in adult patients.

Changes in Laboratory Values: In the first 12 weeks of starting on clarithromycin 500 mg twice a day, 3% of patients has SGOT increases and 2% of patients has SGPT increases > 5 times the upper limit of normal in trial 2 (469 enrolled adult patients) while trial 1 (154 enrolled patients) had no elevation of transaminases. This includes only patients with baseline values within the normal range or borderline low.

Duodenal Ulcer Associated with H. pylori Infection:

In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin, no adverse reactions specific to the combination of these drugs have been observed. Adverse reactions that have occurred have been limited to those that have been previously reported with clarithromycin, omeprazole or amoxicillin.

The adverse reaction profiles are shown below (Table 7) for four randomized double-blind clinical trials in which patients received the combination of clarithromycin 500 mg three times a day, and omeprazole 40 mg daily for 14 days, followed by omeprazole 20 mg once a day, (three studies) or 40 mg once a day (one study) for an additional 14 days. Of the 346 patients who received the combination, 3.5% of patients discontinued drug due to adverse reactions.

Table 7. Adverse Reactions with an Incidence of 3% or Greater

Adverse Reaction	Clarithromycin + Omeprazole (n=346) % of Patients	Omeprazole (n=355) % of Patients	Clarithromycin (n=166) % of Patients Only two of four studies.
Taste Perversion	15	1	16
Nausea	5	1	3
Headache	5	6	9
Diarrhea	4	3	7
Vomiting	4	<1	1
Abdominal Pain	3	2	1
Infection	3	4	2

• 1.Only two of four studies.

Changes in Laboratory Values: Changes in laboratory values with possible clinical significance in patients taking clarithromycin and omeprazole in four randomized double-blind trials in 945 patients are as follows:

Hepatic: elevated direct bilirubin <1%; GGT <1%; SGOT (AST) <1%; SGPT (ALT) <1%,

Renal: elevated serum creatinine <1%.

Less Frequent Adverse Reactions Observed During Clinical Trials of Clarithromycin:

Based on pooled data across all indications, the following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%:

Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocythemia, eosinophilia

Cardiac Disorders: Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations

Ear and Labyrinth Disorders: Vertigo, tinnitus, hearing impaired

Gastrointestinal Disorders: Stomatitis, glossitis, esophagitis, gastrooesophageal reflux disease, gastritis, proctalgia, abdominal distension, constipation, dry mouth, eructation, flatulence

General Disorders and Administration Site Conditions: Malaise, pyrexia, asthenia, chest pain, chills, fatigue

Hepatobiliary Disorders: Cholestasis, hepatitis

Immune System Disorders: Hypersensitivity

Infections and Infestations: Cellulitis, gastroenteritis, infection, vaginal infection

Investigations: Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal

Metabolism and Nutrition Disorders: Anorexia, decreased appetite

Musculoskeletal and Connective Tissue Disorders: Myalgia, muscle spasms, nuchal rigidity

Nervous System Disorders: Dizziness, tremor, loss of consciousness, dyskinesia, somnolence

Psychiatric Disorders: Anxiety, nervousness

Renal and Urinary Disorders: Blood creatinine increased, blood urea increased

Respiratory, Thoracic and Mediastinal Disorders: Asthma, epistaxis, pulmonary embolism

Skin and Subcutaneous Tissue Disorders: Urticaria, dermatitis bullous, pruritus, hyperhidrosis, rash maculo-papular

Gastrointestinal Adverse Reactions:

In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse reactions were reported by patients taking clarithromycin.

All-Cause Mortality in Patients with Coronary Artery Disease 1 to 10 Years Following Clarithromycin Exposure:

In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality was observed in patients randomized to clarithromycin. Clarithromycin for treatment of coronary artery disease is not an approved indication. Patients were treated with clarithromycin or placebo for 14 days and observed for primary outcome events (e.g., all-cause mortality or non-fatal cardiac events) for several years.¹ A numerically higher number of primary outcome events in patients randomized to receive clarithromycin was observed with a hazard ratio of 1.06 (95% confidence interval 0.98 to 1.14). However, at follow-up 10 years post-treatment, there were 866 (40%) deaths in the clarithromycin group and 815 (37%) deaths in the placebo group that represented a hazard ratio for all-cause mortality of 1.10 (95% confidence interval 1.00 to 1.21). The difference in the number of deaths emerged after one year or more after the end of treatment.

The cause of the difference in all-cause mortality has not been established. Other epidemiologic studies evaluating this risk have shown variable results [see Warnings and Precautions (5.5) ].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clarithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System: Thrombocytopenia, agranulocytosis

Cardiac: Ventricular arrhythmia, ventricular tachycardia, torsades de pointes

Ear and Labyrinth: Deafness was reported chiefly in elderly women and was usually reversible.

Gastrointestinal: Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug.

Hepatobiliary: Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin [see Warnings and Precautions (5.2) ].

Infections and Infestations: Pseudomembranous colitis [see Warnings and Precautions (5.6) ]

Immune System: Anaphylactic reactions, angioedema

Investigations: Prothrombin time prolonged, white blood cell count decreased, international normalized ratio increased. Abnormal urine color has been reported, associated with hepatic failure.

Metabolism and Nutrition: Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin.

Musculoskeletal and Connective Tissue: Myopathy rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol [see Contraindications (4.5)and Warnings and Precautions (5.4) ].

Nervous System: Parosmia, anosmia, ageusia, paresthesia and convulsions

Psychiatric: Abnormal behavior, confusional state, depersonalization, disorientation, hallucination, depression, manic behavior, abnormal dream, psychotic disorder. These disorders usually resolve upon discontinuation of the drug.

Renal and Urinary: Nephritis interstitial, renal failure

Skin and Subcutaneous Tissue: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne, acute generalized exanthematous pustulosis

Vascular: Hemorrhage